Is DLST p.Pro159Leu (c.476C>T) pathogenic?

DLST p.Pro159Leu (c.476C>T) is classified Uncertain significance in DLST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-23). AlphaMissense: likely benign (0.1162); Very rare (popmax 0.00178%, nfe).

How common is DLST p.Pro159Leu (c.476C>T) in the general population?

DLST p.Pro159Leu (c.476C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about DLST p.Pro159Leu (c.476C>T)?

AlphaMissense predicts likely benign (score 0.1162) — an in-silico prediction, not a clinical call.

DLST p.Pro159Leu

c.476C>T · rs1307487633 · VCV2550163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1162 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1162	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -12.54	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 3,281 bp · p 1 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,179,888 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00144% 21/1,461,448 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DLST
Protein: p.Pro159Leu
Coding: c.476C>T
MANE Select: NM_001933
dbSNP: rs1307487633
Type: single nucleotide variant
Location: chr14:74892867 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 77.40 · 2 PDB
Residue 159: the 'disordered' region

Full DLST gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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DLST p.Arg4Gln Uncertain significance ★★ ⚠ same type
DLST p.Arg6Ser Uncertain significance ★★ ⚠ same type
DLST p.Asn44Ser Uncertain significance ★★ ⚠ same type
DLST p.Asn51Asp Uncertain significance ★★ ⚠ same type
DLST p.Asp304Gly Uncertain significance ★★ ⚠ same type
DLST p.Gly216Val Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dlst-p-pro159leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown